What causes insulin resistance in adults, particularly those over 45 years old?

What Causes Insulin Resistance

Insulin resistance develops through a complex interplay of genetic predisposition, excess adiposity (particularly visceral fat), physical inactivity, and metabolic dysfunction, with obesity and visceral adipose tissue serving as the primary drivers by releasing inflammatory mediators and excess lipids that impair insulin signaling in muscle, liver, and other tissues. 1

Primary Causative Factors

Obesity and Visceral Adiposity

• Visceral adipose tissue is the critical mediator of insulin resistance, with the Framingham Heart Study demonstrating linear increases in hypertension, impaired fasting glucose, and dyslipidemia across increasing visceral fat quartiles 1
• Adipose tissue releases dysregulated metabolic mediators including adipokines, cytokines, chemokines, excess lipids, and toxic lipid metabolites that promote insulin resistance in other tissues 2, 3
• Visceral adipocytes provoke insulin resistance by promoting extensive lipolysis and release of fatty acids into the splanchnic circulation 4
• Reduced production and release of adiponectin by adipocytes contributes to the pathophysiological process 4

Physical Inactivity and Sedentary Lifestyle

• Physical inactivity is a well-established risk factor for developing insulin resistance 4, 5
• Sedentary lifestyle, in combination with obesity and other genetic or acquired factors, interact to produce insulin resistance 4

Genetic Predisposition

• Insulin sensitivity varies widely among individuals, with moderate genetic influences on the development of insulin resistance 6
• The genetic basis for common forms of insulin resistance is likely polygenic and heterogeneous 6
• Rare mutations in genes for the insulin receptor and peroxisome proliferator-activated receptor gamma can cause extreme forms of insulin resistance 6
• Gene variants may have pleiotropic influences on multiple metabolic syndrome traits, explaining the clustering of these conditions 6

Age-Related Factors

• Age is a significant factor in the development of insulin resistance 7
• The prevalence of metabolic syndrome increases with age, with the highest prevalence in subjects between 60 to 69 years of age 4

Tissue-Specific Mechanisms

Hepatic Insulin Resistance

• Hepatic insulin resistance plays a primary role by promoting de novo lipogenesis and dyslipidemia 4, 1
• The liver manifests insulin resistance relative to the periphery, leading to free fatty acid exportation to muscles to promote muscle insulin resistance 4
• Either impaired hepatic or adipose responses to insulin, or both, can lead to the buildup of circulating free fatty acids 4

Skeletal Muscle Insulin Resistance

• Quantitatively, skeletal muscle is the major site of insulin resistance 8
• Defects in insulin signaling through IRS1, PI3K, Akt2, and AS160/TBC1D4 explain reduced insulin action on glucose transport 8
• Impaired insulin activation of glycogen synthase occurs due to attenuated dephosphorylation at specific sites 8

Pancreatic β-Cell Dysfunction

• Insulin resistance leads to compensatory increase in insulin secretion from pancreatic β-cells 4
• Over time, the capacity of the β-cell erodes, leading to β-cell failure and subsequent type 2 diabetes 4, 1

Secondary and Aggravating Factors

Hormonal Excess

• Several hormones (growth hormone, cortisol, glucagon, epinephrine) antagonize insulin action 4
• Excess amounts of these hormones in conditions like acromegaly, Cushing's syndrome, glucagonoma, and pheochromocytoma can cause insulin resistance 4

Inflammatory Mediators

• Leptin, plasminogen activator inhibitor-1, tumor necrosis factor-α, and other proinflammatory cytokines have been implicated in the pathophysiological process 4
• Stress hormones and mediators of inflammation (interleukin 1 and 6) released during surgical stress may lead to perioperative insulin resistance 4

Metabolic Abnormalities

• Hyperinsulinemia and metabolic syndrome are common concurrent phenotypes in obesity 4
• Alterations in intracellular concentration of intermediates, including ceramide and other lipids, lead to defects in cellular responsiveness to insulin 2

Race and Ethnicity Considerations

• Members of high-risk ethnic populations (African American, Latino, Native American, Asian American, and Pacific Islander) have increased susceptibility to insulin resistance 4, 5
• Asian Americans have increased diabetes risk at lower BMI thresholds (≥23 kg/m² vs ≥25 kg/m²) 5

Critical Clinical Pitfalls

A common pitfall is focusing solely on BMI, as it accounts for only 60% of insulin resistance variance in adults 1. Waist circumference is more strongly associated with visceral fat and serves as an independent predictor of insulin resistance, making it a superior clinical marker 1.

The interaction between body fatness and insulin resistance produces cardiovascular risk greater than either factor alone, emphasizing the need to address both components simultaneously rather than treating them as independent variables 1.

In children and adolescents, pubertal development causes transient physiologic insulin resistance that peaks at mid-puberty and returns to near-prepubertal levels by puberty's end, requiring age-appropriate interpretation 4, 1.